Search tips
Search criteria 


Logo of molmedLink to Publisher's site
Mol Med. 1997 September; 3(9): 593–599.
PMCID: PMC2230084

Inhibition of vascular smooth muscle cell proliferation and intimal hyperplasia by gene transfer of beta-interferon.


BACKGROUND: Balloon injury of the arterial wall induces increased vascular smooth cell proliferation, enhanced elastic recoil, and abnormalities in thrombosis, each of which contribute to regrowth of intima and the lesion of restenosis. Several gene transfer approaches have been used to inhibit such intimal smooth muscle cell growth. In this report, adenoviral gene transfer of beta-interferon (beta-IFN) was analyzed in a porcine model of balloon injury to determine whether a secreted growth inhibitory protein might affect the regrowth of vascular smooth muscle cells in vitro and in arteries. MATERIALS AND METHODS: An adenoviral vector encoding beta-interferon (ADV-beta-IFN) was prepared and used to infect porcine vascular smooth muscle cells in a porcine balloon injury model. Its antiproliferative effect was analyzed in vitro and in vivo. RESULTS: Expression of recombinant porcine beta-IFN in vascular smooth muscle cells reduced cell proliferation significantly in vitro, and supernatants derived from the beta-IFN vector inhibited vascular smooth muscle cell proliferation relative to controls. When introduced into porcine arteries after balloon injury, a reduction in cell proliferation was observed 7 days after gene transfer measured by BrdC incorporation (ADV-delta E1 arteries 14.5 +/- 1.2%, ADV-beta IFN 6.8 +/- 0.8%, p < 0.05, unpaired, two-tailed t-test). The intima-to-media area ratio was also reduced (nontransfected arteries, 0.70 +/- 0.05; ADV-delta E1 infected arteries, 0.69 +/- 0.06; ADV-beta-IFN infected arteries, 0.53 +/- 0.03; p < 0.05, ANOVA with Dunnett t-test). No evidence of organ toxicity was observed, and regrowth of the endothelial cell surface was observed 3-6 weeks after balloon injury. CONCLUSIONS: Gene transfer of an adenoviral vector encoding beta-IFN into balloon-injured arteries reduced vascular smooth muscle proliferation and intimal formation. Expression of this gene product may have potential application for the treatment of vascular proliferative diseases.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Nabel EG, Yang Z, Liptay S, San H, Gordon D, Haudenschild CC, Nabel GJ. Recombinant platelet-derived growth factor B gene expression in porcine arteries induce intimal hyperplasia in vivo. J Clin Invest. 1993 Apr;91(4):1822–1829. [PMC free article] [PubMed]
  • Nabel EG, Shum L, Pompili VJ, Yang ZY, San H, Shu HB, Liptay S, Gold L, Gordon D, Derynck R, et al. Direct transfer of transforming growth factor beta 1 gene into arteries stimulates fibrocellular hyperplasia. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10759–10763. [PubMed]
  • Ohno T, Gordon D, San H, Pompili VJ, Imperiale MJ, Nabel GJ, Nabel EG. Gene therapy for vascular smooth muscle cell proliferation after arterial injury. Science. 1994 Aug 5;265(5173):781–784. [PubMed]
  • Chang MW, Barr E, Seltzer J, Jiang YQ, Nabel GJ, Nabel EG, Parmacek MS, Leiden JM. Cytostatic gene therapy for vascular proliferative disorders with a constitutively active form of the retinoblastoma gene product. Science. 1995 Jan 27;267(5197):518–522. [PubMed]
  • Indolfi C, Avvedimento EV, Rapacciuolo A, Di Lorenzo E, Esposito G, Stabile E, Feliciello A, Mele E, Giuliano P, Condorelli G, et al. Inhibition of cellular ras prevents smooth muscle cell proliferation after vascular injury in vivo. Nat Med. 1995 Jun;1(6):541–545. [PubMed]
  • ISAACS A, LINDENMANN J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci. 1957 Sep 12;147(927):258–267. [PubMed]
  • David M. Transcription factors in interferon signaling. Pharmacol Ther. 1995 Feb;65(2):149–161. [PubMed]
  • Palmer H, Libby P. Interferon-beta. A potential autocrine regulator of human vascular smooth muscle cell growth. Lab Invest. 1992 Jun;66(6):715–721. [PubMed]
  • Min W, Ghosh S, Lengyel P. The interferon-inducible p202 protein as a modulator of transcription: inhibition of NF-kappa B, c-Fos, and c-Jun activities. Mol Cell Biol. 1996 Jan;16(1):359–368. [PMC free article] [PubMed]
  • Yang ZY, Perkins ND, Ohno T, Nabel EG, Nabel GJ. The p21 cyclin-dependent kinase inhibitor suppresses tumorigenicity in vivo. Nat Med. 1995 Oct;1(10):1052–1056. [PubMed]
  • Stephan DJ, Yang ZY, San H, Simari RD, Wheeler CJ, Felgner PL, Gordon D, Nabel GJ, Nabel EG. A new cationic liposome DNA complex enhances the efficiency of arterial gene transfer in vivo. Hum Gene Ther. 1996 Oct 1;7(15):1803–1812. [PubMed]
  • Yang ZY, Simari RD, Perkins ND, San H, Gordon D, Nabel GJ, Nabel EG. Role of the p21 cyclin-dependent kinase inhibitor in limiting intimal cell proliferation in response to arterial injury. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7905–7910. [PubMed]
  • Artursson K, Gobl A, Lindersson M, Johansson M, Alm G. Molecular cloning of a gene encoding porcine interferon-beta. J Interferon Res. 1992 Jun;12(3):153–160. [PubMed]
  • Fukumoto Y, Kawahara Y, Kariya K, Araki S, Fukuzaki H, Takai Y. Independent inhibition of DNA synthesis by protein kinase C, cyclic AMP and interferon alpha/beta in rabbit aortic smooth muscle cells. Biochem Biophys Res Commun. 1988 Nov 30;157(1):337–345. [PubMed]
  • Heyns AD, Eldor A, Vlodavsky I, Kaiser N, Fridman R, Panet A. The antiproliferative effect of interferon and the mitogenic activity of growth factors are independent cell cycle events. Studies with vascular smooth muscle cells and endothelial cells. Exp Cell Res. 1985 Dec;161(2):297–306. [PubMed]
  • Kuo PT, Wilson AC, Goldstein RC, Schaub RG. Suppression of experimental atherosclerosis in rabbits by interferon-inducing agents. J Am Coll Cardiol. 1984 Jan;3(1):129–134. [PubMed]
  • Wilson AC, Schaub RG, Goldstein RC, Kuo PT. Suppression of aortic atherosclerosis in cholesterol-fed rabbits by purified rabbit interferon. Arteriosclerosis. 1990 Mar-Apr;10(2):208–214. [PubMed]
  • Bhattacharya S, Eckner R, Grossman S, Oldread E, Arany Z, D'Andrea A, Livingston DM. Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha. Nature. 1996 Sep 26;383(6598):344–347. [PubMed]
  • French BA, Mazur W, Ali NM, Geske RS, Finnigan JP, Rodgers GP, Roberts R, Raizner AE. Percutaneous transluminal in vivo gene transfer by recombinant adenovirus in normal porcine coronary arteries, atherosclerotic arteries, and two models of coronary restenosis. Circulation. 1994 Nov;90(5):2402–2413. [PubMed]
  • Barr E, Carroll J, Kalynych AM, Tripathy SK, Kozarsky K, Wilson JM, Leiden JM. Efficient catheter-mediated gene transfer into the heart using replication-defective adenovirus. Gene Ther. 1994 Jan;1(1):51–58. [PubMed]
  • Newman KD, Dunn PF, Owens JW, Schulick AH, Virmani R, Sukhova G, Libby P, Dichek DA. Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia. J Clin Invest. 1995 Dec;96(6):2955–2965. [PMC free article] [PubMed]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ